5diuretics class

DIURETICS

• Diuresis: increased urine flow

• Diuretics: substances which elicit diuresis

• In the kidney, water reabsorption dependent primarily on Na+ reabsorption

• Thus a diuretic is an agent which inhibits tubular Na+ reabsorption (along with Cl-, HCO3

-) resulting in increased excretion of these ions

Classification of diuretics A) According to the site of Action: 1) Site –I ( Proximal convoluted tubule) acting drugs :

– Osmotic diuretics: mannitol, isosorbide , urea– Carbonic anhydrase inhibitors : acetazolamide , methazolamide ,

dichlorphenamide – Xanthene drugs : aminophylline , theophylline , theobromide , caffeine 2) Site-II (Ascending limb of loop of Henle) acting drugs:– Furosemide , bumetanide, ethacrynic acid , mefruside, piretanide 3) Site –III ( Distal convoluted tubule )acting drugs :– Thiazides: chlorothiazide, hydrochlorthiazide, benzthiazide ,

hydroflumethiazide , clopamide – Thiazide like( related heterocyclics ) : cholrthalidone , metolazone ,

Xipamide , Indapamide – Mercurials: mercaptomerin, mersibid, mercurophyll, mersalyl4) Site –IV ( Collecting Duct) :– K+ sparing diuretics : spironolactone , triamterene , amiloride

B) According to potency:

1) High ceiling(efficacy) diuretics (loop diuretics)– Furosemide– Bumetanide – Piretanide – Ethacrynic acid – Mefruside

2) Moderate efficacy diuretics ( thiazides )– Hydrochlorthiazide – Bendroflumethiazide 3) Low efficacy diuretics a) Osmotic diuretics :b) Potassium sparing c) Carbonic anhydrase

inhibitors d) Xanthene groups

Proximal Convoluted tubule

• 66% of total sodium ions (Na+, but 85% of the filtered NaHCO3), 65% of the K+, 60% of the water, and virtually all of the filtered glucose and amino acids are reabsorbed.

• Specific transport• Passive transport • Paracellular pathways

Carbonic anhydrase inhibitor: Acetazolamide

• Pharmacokinetics– The carbonic anhydrase inhibitors are well

absorbed after oral administration. An increase in urine pH from the HCO3

– diuresis is apparent within 30 minutes, maximal at 2 hours, and persists for 12 hours after a single dose. Excretion of the drug is by secretion in the proximal tubule S2 segment. Therefore, dosing must be reduced in renal insufficiency

• Mechanism– By inhibiting the action of carbonic anhydrase ,

inhibits reabsorption of sodium– Blocks NaHCO3 reabsorption causing bicarbonate

diuresis – Metabolic acidosis

Clinical Indications

• Glaucoma• Urinary alkalinization.• Metabolic alkalosis• Acute mountain sickness• Premenstrual oedema • Other uses:

– adjuvants in the treatment of epilepsy, in some forms of hypokalemic periodic paralysis, and to increase urinary phosphate excretion during severe hyperphosphatemia.

Toxicity • HYPERCHLOREMIC METABOLIC ACIDOSIS

• RENAL STONES– Phosphaturia and hypercalciuria occur during the bicarbonaturic response to

inhibitors of carbonic anhydrase. • RENAL POTASSIUM WASTING

– Potassium wasting can occur because Na+ presented to the collecting tubule is partially reabsorbed, increasing the lumen-negative electrical potential in that segment and enhancing K+ secretion. This effect can be counteracted by simultaneous administration of potassium chloride.

• OTHER TOXICITIES– Drowsiness and paresthesias are common following large doses of acetazolamide.

Carbonic anhydrase inhibitors may accumulate in patients with renal failure, leading to nervous system toxicity. Hypersensitivity reactions (fever, rashes, bone marrow suppression, and interstitial nephritis) may also occur.

Mannitol

• Sugar alcohol• Characters :– Freely filtered – No absorption– Pharmacologically inert– IV administration– Entire tubule

• Indications :– Glaucoma – Cerebral oedema – Prevention of acute

renal failure – Before neurosurgery to

reduce CSF and intraocular pressure

– Oliguric states ( rhabdomyolysis)

• Contraindications :– Anuria (risk of cardiac

failure )– Marked pulmonary

congestion– Prevention of acute

renal failure – Intracranial hemorrhage

• Adverse effects :– Transeint expansion of

ECF volume – Hyponatremia – Headche , nausea ,

vomiting

Loop of henle

• action of the transporter contributes to excess K+ accumulation within the cell. Back diffusion of this K+ into the tubular lumen causes a lumen-positive electrical potential that provides the driving force for reabsorption of cations—including magnesium and calcium—via the paracellular pathway

Loop diuretics

• Pharmacokinetics– rapidly absorbed. – eliminated by the kidney by glomerular filtration and tubular

secretion. – Absorption of oral torsemide is more rapid (1 hour) than that of

furosemide (2–3 hours) and is nearly as complete as with intravenous administration.

– The duration of effect for furosemide is usually 2–3 hours and that of torsemide is 4–6 hours.

– Half-life depends on renal function.– Reduction in the secretion of loop diuretics may result from

simultaneous administration of agents such as NSAIDs or probenecid, which compete for weak acid secretion in the proximal tubule.

Characters :– Very potent – Can act in severe renal and heart failure where

other diuretics fail– Rapid onset

Mechanism: – inhibit NKCC2, the luminal Na+/K+/2Cl– transporter

in the thick ascending limb of Henle's loop– Decrease intracellular K, back diffusion, positive

potential, increase diuresis– induce synthesis of renal prostaglandins– increase renal blood flow– Massive dose inhibits carbonic anhydrase

Indications

• Acute pulmonary oedema• Moderate hypertension• Left ventricular failure • Congestive heart failure • Oedema due to liver cirrhosis • Oliguric phase of acute renal failure • Hypercalcemia • Hyperkalemia • anion overdose (treating toxic ingestions of bromide,

fluoride, and iodide, which are reabsorbed in the thick ascending limb)

Toxicity

• Hypokalemic metabolic alkalosis• Ototoxicity• Nephrotoxicity • Myalgia • Hyperuricemia• Hypomagnesemia• Hypovolemia • severe dehydration. Hyponatremia • Hypovolemic hypotension• Allergic & other reactions

– Except for ethacrynic acid, the loop diuretics are sulfonamides. Therefore skin rash, eosinophilia and, less often, interstitial nephritis are occasional side effects of these drugs. This toxicity usually resolves rapidly after drug withdrawal. Allergic reactions are much less common with ethacrynic acid.

– Cross allergenicity with thiazides, sulfonamides

Contraindication• hepatic cirrhosis, borderline renal failure, or

heart failure• Gout• Anuric renal failure • Pregnancy Drug Interactions :– Digoxin– Aminoglycosides – Cephalosporins – Warfarin

Distal convoluted tubule • K+ does not recycle across the

apical membrane of the DCT as it does in the TAL, there is no lumen-positive potential in this segment, and Ca2+ and Mg2+ are not driven out of the tubular lumen by electrical forces. Instead, Ca2+ is actively reabsorbed by the DCT epithelial cell via an apical Ca2+ channel and basolateral Na+/Ca2+ exchanger (Figure 15–4). This process is regulated by parathyroid hormone.

Thiazides

• Pharmacokinetics – All of the thiazides can be administered orally– Chlorothiazide, the parent of the group, is not very

lipid-soluble and must be given in relatively large doses. It is the only thiazide available for parenteral administration.

– Chlorthalidone is slowly absorbed and has a longer duration of action.

– Although indapamide is excreted primarily by the biliary system, enough of the active form is cleared by the kidney to exert its diuretic effect in the DCT

Pharmacodynamics

• Thiazides inhibit NaCl reabsorption from the luminal side of epithelial cells in the DCT by blocking the Na+/Cl– transporter (NCC).

• ATP dependent K channel openers • Enhance Calcium reabsorption by two ways :– In the proximal tubule, thiazide-induced volume depletion

leads to enhanced Na+ and passive Ca2+ reabsorption. – In the DCT, lowering of intracellular Na+ by thiazide-induced

blockade of Na+ entry enhances Na+/Ca2+ exchange in the basolateral membrane and increases overall reabsorption of Ca2+

Indications

(1) hypertension, (2) heart failure, (3) nephrolithiasis due to idiopathic

hypercalciuria, and (4) nephrogenic diabetes insipidus.

Toxicity

• HYPOKALEMIC METABOLIC ALKALOSIS AND HYPERURICEMIA• IMPAIRED CARBOHYDRATE TOLERANCE

– Hyperglycemia may occur in patients who are overtly diabetic or who have even mildly abnormal glucose tolerance tests. The effect is due to both impaired pancreatic release of insulin and diminished tissue utilization of glucose. Hyperglycemia may be partially reversible with correction of hypokalemia.

• HYPERLIPIDEMIA– Thiazides cause a 5–15% increase in total serum cholesterol and low-density lipoproteins (LDL). These

levels may return toward baseline after prolonged use.• HYPONATREMIA

– It is due to a combination of hypovolemia-induced elevation of ADH, reduction in the diluting capacity of the kidney, and increased thirst. It can be prevented by reducing the dose of the drug or limiting water intake.

• ALLERGIC REACTIONS– The thiazides are sulfonamides and share cross-reactivity with other members of this chemical group.

Photosensitivity or generalized dermatitis occurs rarely. hemolytic anemia, thrombocytopenia, and acute necrotizing pancreatitis.

• OTHER TOXICITIES– Weakness, fatigability, and paresthesias similar to those of carbonic anhydrase inhibitors may occur.

Impotence has been reported but is probably related to volume depletion

Collecting tubule

• The principal cells are the major sites of Na+, K+, and water transport and the intercalated cells are the primary sites of H+ secretion

• principal cells do not contain cotransport systems for Na+ and other ions in their apical membranes

Potassium sparing diuretics : spironolactone

• Aldosterone antagonist • Steroid chemically related to mineralocorticoid aldosterone Mechanism of ALDOSTERONE ACTION• By combining with aldosterone receptor , promotes gene

mediated mRNA synthesis, induces the formation of aldosterone induced proteins which promote Na+ reabsorption by :– Activating sodium channel – Translocating sodium channels from cytosolic site to luminal

membrane and Na/K ATPase to basolateral membrane – Increase ATP production by mitochondria

Spironolactone competitively inhibits the formation of aldosterone induced proteins (AIPs) and blocks all the action of aldosterone in the principal cell of the collecting duct.

• Pharmacokinetics :– High oral bioavailability– Highly bound to plasma proteins – Completely metabolised in liver , converted to

active metabolites –canrenone .– Undergoes some enterohepatic circulation

• Indications – Edema – Hyperaldosteronic states – Adjunct to other

diuretics – Antiandrogenic to treat

women with hirsuitism or significant acne

– Congestive heart failure – Hypertension

• Adverse effects – Hyperkalemia – Acidosis – Antiandrogen ( male

gynecomastia)– Drowsiness– Confusion – Abdominal upset– Impotence – Menstrual irregularities– Peptic ulcer

Renal epithelial sodium channel blockers

• Amiloride , triamterene

Bind to the sodium channel from the luminal side and block it, reducing the lumen negative transepithelial potential difference responsible for K+ And H+ secretion and indirectly inhibit K excretion.

Triamterene is metabolized in the liver, but renal excretion is a major route of elimination for the active form and the metabolites.

triamterene has a shorter half-life and must be given more frequently than amiloride (which is not metabolized).

Triamterene:• Bioavailability :30-70%• Protein binding: 67%• Metabolism: conjugated to hydroxytriamterene• Half-life: 1-2 hours, active metabolite 3 hours• Excretion: renal <50%, 21% unchanged

Amiloride:Bioavailability: Readily absorbedMetabolism: noneHalf-life :6 to 9 hoursExcretion :unchanged in urine